The overall aim of this project is to design and build a state-of-the-art camera system, based on a Direct Detection Active Pixel Detector (APD) to provide a vastly improved film substitute for direct digital recording of data for biological Electron Microscopy. Such a system will be immediately applicable and beneficial to cryo-Electron Microscopy (cryo-EM) of macromolecules. The new APD will have an extremely uniform surface and format of 3500x4000 pixels at 5 micron x 5 micron pitch. As a direct incident electron detector, this device will not require a resolution limiting phosphorescent scintillation screen. Each pixel of the APD will have a diode that will collect the charges deposited by an incident electron in its passage through a sensitive p-epitaxial layer. It will integrate the collected charges during an exposure period. At the conclusion of the frame, the contents of the sensor array are then read out, digitized and stored. All of the integration and read out electronics are implemented within less than 1 micron of the surface of a 0.25 micron CMOS chip, and are transparent to the incident electrons. The "fill factor" i.e. the proportion of each pixel area that is sensitive to the incident electrons, is 100% due to the fact that the sensitive p-epitaxial layer lies beneath the readout circuitry and is continuous. We have made a big breakthrough with the realization of a prototype APD having 512 x 550 pixels of 5 micron pitch. This detector yields a signal-to-noise ratio for each incident electron (in the 100-400 keV range) of 10/1 approximately (versus 1/1 with a CCD). The spatial resolution is also much better (2.5 micron versus 30 micron for FWHM). The better spatial resolution allows this detector to take pictures at a much lower magnification than with a CCD. Funding is requested to make larger chips (up to 3.5K x 4K pixels) with on chip ADC allowing very high frame readout (up to 100 frames/sec). Funding is requested also to experiment with even smaller pixel pitch (3 micron x 3 micron). When finished, this kind of detector will allow researchers to quickly gather data on hundreds of thousand of images, greatly improving the resolution of 3D structures of the studied macromolecules. This detector will greatly help the studies of spherical viruses that infect mammalian, insect, and plant hosts. These studies will yield very critical results in the fight against disease.